Anti-spasmodics specific for upper gastrointestinal pain and spasm



United States Patent fiic ANTI-SPASMODICS SPECIFIC FOR UPPER GAS- TROINTESTINAL PAIN AND SPASM John H. Biel, Milwaukee, Wis., assignor to Lakeside Laboratories, Inc., a corporation of Wisconsin No Drawing. Continuation of application Serial No. 217,413, March 24, 1951. This application April 8, 1957, Serial No. 651,166

14 Claims. (Cl. 16765) This invention relates to an ester of cyclic aminoalcohols and particularly to the diphenyl acetic acid ester of N-lower alkyl-3-hydroxypiperidine, non-toxic acid addition salts and non-toxic quaternary ammonium salts thereof, and pharmaceutical compositions of the same.

This application is a continuation of application Serial No. 217,413, filed March 24, 1951, which is a continuation-in-part of application Serial No. 180,295 filed August 18, 1950, now abandoned.

The reduction of smooth muscle spasm, whether of musculotropic or neurotropic origin, by atropine and by various synthetic compounds related in structure to atropine or papaverine, is well known. While many of those compounds will eifectively abolish one or the other type of spasm, they are not capable of relieving both types of muscle spasm. Furthermore, the action of the known compounds is usually accompanied by undesirable side effects such as dilation of the pupil of the eye, dryness of the mouth, large increase in rate of heart beat, hypertension, nausea and vomiting.

Some esters of N-a1kyl-4-piperidinol have been found to be active anti-spasmodics or spasmolytics, but such esters have never been put into use. It is well known that changes in the positions of certain substituents on the piperidine ring may produce profound diflerences in the physiological activity and effects of such compounds, which dilferences are not predictable. Thus, N-methyl- 4-phenyl-4-propionoxy-piperidine is a potent analgesic whereas the corresponding N-methyl-Z-phenyl-Z-propionoxy-piperidine has only slight analgesic properties and beta-4-methyl-piperidine-ethyl benzoate has considerable anesthetic action while the 2 and 3-methyl derivatives have no such action. Hence it will be seen that shifting a group from the 4-position of the piperidine ring may cause complete loss of activity.

It is, therefore, an object of the present invention to provide a compound for pharmaceutical purposes and having the effect of reducing either involuntary muscle or nervous spasm.

Another object of the invention is to provide a com pound having an anti-spasmodic effect in humans, which compound is long lasting in action and which will have only a few undesirable side reactions of minor importance.

A further object of the invention is to provide a series of substituted acetic acid esters of N-lower alkyl-3- piperidinol having longer activity and side reactions both less in number and of lower intensity than'other compounds now in usefor reducing spasm of human muscle or nerves.

I have found that the N-lower alkyl-B-piperidyl diphenyl acetates of the formula wherein R is a lower alkyl, particularly methyl or ethyl, when administered in the form of non-toxic acid addition salts or non-toxic onium salts are effective anti-.spas-v modics in both musculotropic and neurotropic spasms and have long duration of action with fewer undesirable side effects than various other anti-spasdomics now used.

These novel compounds are specific for upper gastronintestinal pain and spasm. They are useful against spasm of the gastroduodenal and biliary tracts, even after failure of response to other prior art anti-spasmodics. The compounds are also very useful for the treatment of cardiospasm, pylorospasm, spasm of biliary sphincter, biliary dyskinesia, gastric neurosis and irritability, and as adjunctive therapy in some inflammatory hypermotility states. In general, the compounds produce normal viscus tone without constipation, urinary retention, dry mouth, and blurring of vision.

For the uses described in the'previous paragraph it is recommended that non-toxic acid addition salts of the tertiary base be employed. Both in. animals and man these compounds are safe. One of the compounds, N- ethyl-S-piperidyl diphenylacetate hydrochloride, has had extremely extensive testing in animals and man. At 20 lug/kg. parenternally and mg./kg. orally this compound was found non-toxic after 8 months administration. In extensive clinical studies no effects have been observed on blood pressure, electrocardiogram, blood counts and biochemical determinations. No clinical manifestations of toxicity, acute or chronic, have been observed.

N-ethyl-3-piperidyl diphenylacetate hydrochloride has about 1% of the activity of atropine yet it is so devoid of adverse side effects and free of toxic manifestations that it can be administered in large enough doses to pro duce the desired results. The recommended dosage is 50 mgm. q.i.d. although lower or higher amounts may be administered as indicated.

N ethyl 3 piperidyl diphenylacetate hydrochloride was formed by heating equimolecular amounts of N-ethyl-3-piperidinol and diphenylacetyl chloride in the presence of a solvent for the reactants. The hydrochloride salt was precipitated and was readily purified by recrystallization from a suitable solvent. The free base, N-ethyl-3-piperidyl diphenylacetate, was obtained as an oily material by treating the said hydrochloride with sodium hydroxide.

N ethyl 3 piperidyl diphenylacetate methiodide was formed by treating free N-ethyl-3-piperidyl-diphenylacetate in an ether solution with methyl iodide.

N-methyl-3-piperidyl-diphenylacetate and its hydrochloride salt differ from the preceding composition by the substitution of a methyl group on the nitrogen of the piperidine ring. The base was made by refluxing N- methyl-3-piperidinol with diphenylacetyl chloride and pyridine. The refluxed material is neutralized and extracted with ether. The extract was dried, the ether removed and the base recovered by vacuum distillation. A solution of the base in ethereal hydrochloric acid pre cipitated the hydrochloride salt in crystalline form.

The following examples illustrate the preparation of some of the compounds provided by this invention:

A. Preparation of N-ethyl-3-piperidyl diphenylacetate, and its related compounds To obtain the free base, 34 g. (0.256 mole) of N-ethyl- S-piperidinol and 20 g. (0.22 mole) of diphenylacetyl chloride were mixed in 80 cc. of isopropanol and the solution was refluxed for two hours. The isopropanol was evaporated in vacuo at 30 mm. pressure, the residue was dissolved in cc. of water and the aqueous solution was extracted several times with ether. The aqueous solution was then neutralized with potassium carbonate Patented Dec. 22,- 1.959,

hydroxide.

and the ether was removed by distillation. N-methyl-3- and extracted with ether. The ethereal solution was dried over anhydrous potassium carbonate and the ether removed by distillation. The product was then distilled at its boiling point180-181 C. at 0.13 mm. of mercury whereby 14 g. of a clear yellow, viscous liquid was obtained. The nitrogen content for C H NO was calculated as 4.33% and the nitrogen content found was 4.21%. The structural formula for the free base is:

A mixture of 4.5 g. (0.02 mole) of diphenylacetyl chloride and 2.6 g. (0.02 mole) of N-ethyl-3-piperidinol were dissolved in 50 cc. of acetone and refluxed for three hours. The precipitate was filtered out and washed. The precipitate was then dissolved in isopropyl alcohol and recrystallized, a single recrystallization yielding N- ethyl-3-piperidyl-diphenylacetate hydrochloride melting at 173-174 C. The yield was 4.2 g. (60% of theoretical). The salt is water soluble and ether insolubleand has a high melting point. The structural formula for the above salt is:

H o-o-o S l 0211s CH3 The calculated iodine content of C H NIO is 27.3% and the content found was 27.7%. The calculated nitrogen content of the above compound is 3.04% and the content found was 2.98%.

B. Preparation of N-melhyl-3-piperidyl-diphenylacetate hydrochloride, and its related compounds 3-hydroxy pyridine was catalytically reduced (by the method of Chen-Heng Kao disclosed in volume 44 of Chemical Abstracts, page 3993(2) to 3-hydroxy-piperidine with a boiling point of 6769 C. at 2 mm. of mercury pressure. 9.0 g. (0.09 mole) of 3-hydroxy-piperidine were mixed with 13.1 g. (0.25 mole) of 88% formic acid and 8.9 g. (0.11 mole) of 37% formaldehyde solution 'and the mixture was refluxed for twenty-four hours. After addition of 5 ml. of concentrated hydrochloric acid, the mixture was distilled at 30 mm. mercury pressure to remove all volatiles. The residue was dissolved in 20 ml. water and the solution was saturated with potassium The solution was then extracted with ether I i 4 4 Y hydroxy-piperidine was obtained by distillation and had a boiling point of 81 C. at 15 mm. of mercury. The yield was 7.0 g. (67% of theoretical). The N content for C H NO was calculated as 11.92% and a content of 11.75% was found.

To obtain N-methyl-3-piperidyl-diphenylacetate, 4.5 g. of N-methyl-3-hydroxy-piperidine (0.039 mole) was mixed with 9.0 g. of diphenyl-acetylchloride (0.039 mole) and 50 cc. of dry pyridine which was used as a solvent and was therefore in large molar excess. The mixture was refluxed for four hours and 200 ml. of water containing 30 g. of sodium bicarbonate was added. The solution was extracted with ether and dried with potassium carbonate.

For the purposes to which the present compounds are to be put, it is recommended that compounds of the formula: I

OO O-CH be used wherein R is ethyl, R is hydrogen or a lower alkyl and X is chlorine, bromine, iodine or the sulfate radical.

However, it is well known that the anti-spasmodic activity of compounds such as the salts disclosed herein, is due to the ester portion of the molecule and not to the acid or alkylating agent used to form the salts. Hence, it will be understood that various salts other than those disclosed may be readily made and used. Some 'such other additional salts include the hydrobromide, methyl iodide, ethyl chloride, maleate, succinate, tartrate, benzoate and phosphate. These and related salts are readily prepared from the free base and the corresponding acid or alkylating agent in solvents such as acetone, benzene, ether type compounds, ethanol, isopropyl, or other alcohols.

Pharmaceutical formulations are usually prepared of a predetermined amount of one of the described compounds, generally in the form of a non-toxic salt. Such formulations may be made into powders, solutions, capsules or tablets. Carriers such as starch, sugar, talc and water may be used in such fomulations. Binders such as gelatin, and lubricants such as sodium stearate, may be used to form tablets. Disintegrating agents such as sodium bicarbonate may also be included in tablets.

Various changes and modifications of the invention can be made and, to the extent that such variations incorporate the spirit of this invention, they are intended to be included within the scope of the appended claims.

What is claimed is:

1. A pharmaceutical composition in unit dosage form adapted for human antispasmodic treatment without causing significant dryness of the mouth and dilation of the eye pupil comprising a member of the group consisting of compounds of the formula non-toxic acid addition salts, and non-toxic quaternary ammonium salts thereof, wherein R is a lower alkyl group, and a pharmaceutical carrier.

2. A pharmaceutical composition in unit dosage form adapted for human antispasmodic treatment without causing significant dryness of the mouth and dilation of the eye pupil comprising a non-toxic acid addition salt of N-ethyl-3-piperidyl diphenylacetate and a pharmaceutical carrier.

3. A pharmaceutical composition in unit dosage form adapted for human antispasmodic treatment without causing significant dryness of the mouth and dilation of the eye pupil comprising a non-toxic quarternary ammonium salt of N-ethyl-3-piperidyl diphenylacetate and a pharmaceutical carrier.

4. A pharmaceutical composition in unit dosage form adapted for human antispasmodic treatment without causing significant dryness of the mouth and dilation of the eye pupil comprising N-ethyl-3-piperidyl diphenylacetate hydrochloride and a pharmaceutical carrier.

5. The process which comprises administering a compound to a human for its therapeutic antispasmodic effect, without causing significant dryness of the mouth and dilation of the eye, said compound being of the group con sisting of compounds of the formula 8. The process which comprises administering N-ethyl 3-piperidyl-diphenylacetate sulfate to a human for its therapeutic antispasmodic effect without causing significant dryness of the mouth and dilation of the eye.

9. A member of the group consisting of compounds of the formula OOC-CH References Cited in the file of this patent UNITED STATES PATENTS 2,079,962 Miescher et al. May 11, 1937 2,143,491 Miescher et a1. Jan. 10, 1939 2,265,185 Miescher et al. Dec. 9, 1941 2,533,002 Feldkamp Dec. 5, 1950 OTHER REFERENCES McElvain et al.: J.A.C.S., vol. 70, January 1948, pp. 1826-28.

Ford-Moore et a1: J.C.S. (London), 1947, pp. 5560. US. Disp., 25th ed., 1955, pp. 1783-90, Lippincott Co. Burtner et. al.: J.A.C.S., vol. 65, 1943, pp. 262-267. 

1. A PHARMECEUTICAL COMPOSITION OF UNIT DOSAGE FORM ADAPTED FOR HUMAN ANTISPASMODIC TREATMENT WITHOUT CAUSING SIGNIFICANT DRYNESS OF THE MOUTH AND DILATION OF THE EYE PUPIL COMPRISING A MEMBER OF THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA 